This project will evaluate the therapeutic activity and mechanism of action of recombinant ovine Interferon tau (IFN/tau) in collagen-induced arthritis (CIA), an experimental animal model of rheumatoid arthritis (RA). Although IFN/tau is a Type I interferon, in contrast to IFNalpha and IFNbeta, IFN( is orally active and induces a Th2 cytokine profile across multiple species. Preliminary experiments indicate that orally administered IFN/tau can prevent CIA as well as experimental allergic encephalomyelitis in mice. Moreover, in Phase I clinical trials in patients with both viral and autoimmune diseases, oral IFN( was extremely well tolerated and caused fewer side effects than injected IFNalpha or IFNbeta. We hypothesize that IFN/tau will induce a systemic Th2 response in mice sensitized to collagen and reduce synovitis when administered after the onset of overt disease. In the proposed project oral IFN/tau will be evaluated in a range of doses for its therapeutic effect on CIA in DBA mice. The mechanism responsible for the anti-inflammatory effect of IFN/tau will be explored by comparing cytokine production in vitro in response to type II collagen in treated and control mice. The results of these experiments should establish the therapeutic activity of IFN/tau in CIA and provide the basis for evaluating it clinically in RA.